Aaron Miller

Interdisciplinary Training

Aaron Miller

"Multiplexed mutation rate analysis for prediction of Lynch syndrome risk"

Defects in DNA mismatch repair (MMR) cause one of the most common heritable and deadly
forms of cancer, known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch
syndrome. My work with Maitreya Dunham aims to develop multiplexed diagnostic tools to
assess disease risk for thousands of missense alleles of the mismatch repair genes in parallel. I
have previously exploited continuous cultures to quantify the mutation rate for pools of alleles
simultaneously in yeast. My proposed work seeks to use this novel approach to identify the
extent and basis of pathogenicity for MSH2 and MSH6 variants’ individual and combined effect
on mutation rate. A second and essential component of this project is to determine the positive
predictive value for mutation rates and status as a dominant or recessive mutation on disease
risk in humans. Current databases that hold information on genotypes implicated in Lynch
Syndrome do not contain detailed information related to disease severity such as age of
onset/diagnosis. Under the guidance of Polly Newcomb, epidemiologist and colorectal cancer
researcher at FHCRC, I have begun to mine the clinical literature and raw data from medical
studies for which alleles confer early onset or increased severity in Lynch syndrome patients.
When combined these two approaches have the potential to identify both high and low risk
alleles and may help guide clinicians in treatment of Lynch syndrome. In the process, we are
creating general approaches that may be useful in studying a variety of cancer and complex
traits as a whole.